Despite the high frequency of aneuploidy in man, little is known about the mechanisms by which chromosome imbalance results in reduced viability and abnormalities of morphogenesis and mental function. The overall objective of this work is to elucidate the mechanisms responsible for the deleterious effects of aneuploidy. A comprehensive biochemical, embryological, and genetic approach will be used. Recent work has demonstrated a strict gene dosage effect for soluble enzymes in trisomic situations. The present proposal is directed toward extentsion of these analyses to cell surface proteins which may be instrumental in developmental processes, to the examination of the biochemical and developmental effects of monosomy, and to the investigation of the general effects of aneuploidy on the synthesis of cell proteins. The first two of these studies will be undertaken to complete the validation of the dosage hypothesis for the direct effects of aneuploidy, while the second and third are aimed at testing the hypothesis that chromosome imbalance may cause widespread regulatory abnormalities which affect the synthesis of a large number of cellular proteins. An understanding of the mechanisms by which aneuploidy disturbs development and cell function will permit more rational approaches to the identification and management of affected individuals and is directly relevant to an understanding of the fundamental mechanisms of genetic expression and control in man.